Differential selective pressures on the merozoite surface protein 2 locus of Plasmodium falciparum in a low endemic area

Abstract

195 Plasmodium falciparum merozoite surface protein-2 alleles collected in Tak Province, Thailand, in 1996 and 2006 revealed extremely limited sequence polymorphism except in the variable (V) region, which defines the two allelic families 3D7 and FC27. This pattern is most easily explained by repeated inter-allelic gene conversion events homogenizing alleles outside the V region. Comparison of synonymous and nonsynonymous differences in V regions within allelic families supported the hypothesis that amino acid sequence polymorphism in this region is selectively favored. The pattern of sequence differentiation supported the hypothesis that repeats in the V region have evolved by concerted evolution in the 3D7 family but not in the FC27 family. In the FC27 family two alleles of relatively high frequency were the most common V-region alleles in both 1996 and 2006, while 3D7 alleles constituted a significantly greater proportion of the sequences collected in 2006 (56.1%) than of those collected in 1996 (28.9%). These changes in the frequencies of 3D7 alleles may reflect increased intensity of selection on the P. falciparum population in Thailand as a result of effective control measures that have sharply reduced the incidence of malaria infection.

Figure 1

(A) Schematic representation of the major regions of the P. falciparum MSP-2 protein.: SP = signal peptide; C1 = conserved region 1; V = variable region; C2 = conserved region 2; PRO = propeptide. (B) Schematic representation of the V region of members of the 3D7 allelic family: NR = non-repeat; p-T = poly T. (C) Schematic representation of the V region of members of the FC27 allelic family: NR = non-repeat; R1 = repeat region 1; R2 = repeat region 2.

Figure 2

Plot of V-region allele frequencies in 2006 vs. 1996, for alleles in the two allelic families (3D7 and FC27) that were present in both years. In the case of the 3D7 family, there was not a significant correlation between frequencies in the two years (r_S = 0.661: n.s.). In the case of the FC27 family, there was a highly significant correlation between frequencies in the two years (r_S = 0.963; P < 0.001).

Figure 3

Schematic representation of the patterns observed in the alignment of repeat regions in the FC27 family: (A) the three repeat types (A–C) in the R1 repeats; and (B) the five repeat types (A–E) in the R2 repeats.

Figure 4

Haplotypes in the C2 region of pfmsp-2. Lines connecting haplotypes correspond to a single point-mutational step. The percentage of occurrence of each haplotype with 3D7 and FC27 family V regions is also shown.